Cannabinoids derived from marijuana are known to adversely affect reproductive functions of both males and females in humans and/or laboratory mammals. We recently reported that delta-9-tetrahydrocannabinol (THC) and other cannabinoids (cannabinol, CBN and cannabidiol, CBD) can also directly affect the process of fertilization by reducing the fertilizating capacity of sea urchin sperm. These cannabinoids do not appear to reduce sperm motility. The adverse effects of these drugs on sperm fertility are reversible. We postulate that cannabinoids reduce sperm fertility by affecting one or more processes associated with the acrosome reaction. Using sea urchin gametes as a model system we propose to investigate the effects of THC, CBN and CBD on: 1) stimulation of the acrosome reaction by egg jelly which contains a specific ligand that is the natural inducer of the acrosome reaction; 2) artificial induction of the acrosome reaction by stimulating agents (calcium ionophore A23187 and ammonia, etc.) which by-pass sperm surface receptors; 3) ion fluxes involved in triggering the acrosome reaction; 4) other manifestations of sperm activation (swarming, increased respiration and increased motility) that are normally stimulated by other specific ligands in the egg jelly; 5) the activities of plasma membrane adenyl cyclase and guanylate cyclase which are involved in sperm activation; 6) the ability of acrosome reacted sperm to bind to species specific receptors on the egg surface; 7) the activities acrosomal hydrolases (aryl sulfatase, serine protease, and phospholipase A) which mediate sperm penetration into the egg; and 8) metabolism of arachidonic acid to produce oxidation products that modulate sperm fertility. The above aims are intended to identify the targets for the cannabinoid effects on sperm fertility which will enable us to design future proposals to establish molecular mechanisms. The results of these studies will also provide the basis for future in vitro examination of possible direct effects of cannabinoids on fertilization in laboratory mammals and humans. Since sperm functions during fertilization involve cellular processes that are common to all kinds of cells, this information might provide new insights as to how cannabinoids affect the function of human somatic cells as well.